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A tumor's support system — its existing blood vessels, or vasculature — nourishes the tumor by supplying oxygen and nutrients, allowing it to grow, spread, and often turn lethal. Antiangiogenesis approaches attempt to prevent the formation of these blood vessels, but researchers are also focused on targeting the established vasculature in hopes of destroying tumors by obliterating the blood vessel underpinnings that support them. Vascular disrupting agents (VDAs) work by causing the endothelial cells, cells that line the inside of blood vessels, to change shape and collapse. This action shuts off blood fl ow to tumors, leading to cell death. " You don't, by any means, have to affect all the endothelial cells in a vessel, " explained Dietmar W. Siemann, Ph.D., a radiation oncologist at the University of Florida in Gaines-ville. " All you have to do is cause a collapse by damaging some part of the vessel. Everything downstream will not get its nutritional supply or clear waste products, so the tumor cells will die. " Researchers are pursuing two types of VDAs — small molecule and ligand directed. The intended result of both classes of VDAs is the same, but their approaches are different. Small-molecule VDAs damage the structure of endothelial cells by interfering with the cells' cellular scaffolding, or tubulin. Tubulin is a protein composed of micro-tubules, a minute fi lament that helps cells maintain their shape. Some small-molecule VDAs cause the release of tumor necrosis factor, which leads to the collapse of blood vessels. Small-molecule VDAs have made the greatest progress in the clinic, Siemann said. Ligand-directed VDAs use antibod-ies, peptides, or growth factors to target toxins or procoagulants to the tumor en-dothelium. The idea behind this approach is that endothelial cells in tumor blood vessels express receptors on their surfaces that are unique to the tumor vessels. Researchers are trying to identify these receptors to target them with drugs, monoclonal antibodies, or gene therapy, which would cause their collapse. The overall goal of VDAs is specifi-city, something that is hard to come by in many of today's cancer treatments. Rather than obliterate cancer cells and surrounding nonmalignant cells, VDAs would go straight to the endothelia of tumor blood vessels and destroy them, while leaving surrounding tissue untouched. Several companies are conducting preclinical studies and early phase trials with VDAs. So far, research has shown that these agents alone do not have a substantial effect …

Taking Down Tumors: Vascular Disrupting Agents Entering Clinical Trials